Carbamate sedative compositions and method of use



United Sttes eat hie 3,3i3,6% Patented Apr. 11, 1967 3,313,696 CARBAMATESEDATIVE COMPUSTTEGNE AND METHUD OF USE Charles D. Bossinger, Kankahee,and Kelley G. Taylor, Decatur, 111., assignors to Armour PharmaceuticalCompany, Chicago, 111., a corporation of Delaware No Drawing. Originalapplication June 26, 1962, Ser. N 205,201. Divided and this appiicationAug. 24, 1964, Ser. No. 391,769

9 Claims. (Cl. 167--65} This invention relates to sedative compositionsand to a method of treating the central nervous system of animals, i.e.,mammals and fowls, especially man and domestic animals by administeringthese compositions to those animals.

This application is a divisional application from copending applicationSer. No. 205,201, filed June 26, 1962 which is continuation-in-part ofcopending application Ser. No. 729,554, filed Apr. 21, 1958 and of Ser.No. 38,763, filed June 27, 1960. Application Ser. No. 38,763 was acontinuation-in-part of application Ser. No. 729,553, filed Apr. 21,1958, and applications Ser. Nos. 729,553 and 729,554 werecontinuations-in-part of parent application Ser. No. 554,132, filed Dec.20, 1955. Applications Ser. Nos. 554,132, 729,553, 38,763 and 205,201are now abandoned.

It is an object of this invention to provide carbamate compounds for usein treating the central nervous system which function primarily asshort-acting sedatives. Another related object is to provide carbamatecompounds which exhibit a marked sedative action with a minimum oftranquilization and muscle relaxation. Further objects and advantageswill be indicated in the following detailed specification.

The hydroxy phenyl alkyl carbamate compounds which are useful in thetreatment of the central nervous system in accordance with the presentinvention all contain a secondary alcohol group and are characterized bythe following structural formula:

In the foregoing formula, R is an alkyl group containing from 1 to 2carbon atoms. Specific examples of such compounds are l-hydroxy-l-phenylbutyl-Z-carbarnate, and l-hydroxy-l-phenyl propyl-Z-carbamate. Thepreferred compound for use as a short-acting sedative in accordance withthe present invention is l-hydroxy-lphenyl butyl-Z-carbamate.

The foregoing carbamate compounds can be prepared by the processdescribed in copending application Ser. No. 816,700, filed May .29,1959, now US. Patent No. 3,066,-

164. In the process as described therein, a 1,2-glycol is converted .tothe corresponding carbonate, and the car bonate is subjected toammonolysis to obtain the desired carbamate. Preferably, 1,2-glycol iscondensed with a halo-forrnic ester to obtain an acyclic carbonate whichis then subjected to ammonolysis to obtain the monocarbamate. Since theparticular process for preparing the carbamate compounds does not form apart of the present invention, it is not believed it will be necessaryto further describe such processes herein, except as illustrated by thefollowing examples.

In utilizing the compounds of this invention for central nervous systemtreatment and particularly for use as shortacting sedatives, it ispreferred to administer the compounds orally. Since the compounds arewell-absorbed orally, it will usually not be necessary to resort toparenteral administration. For oral administration, it is preferred tocombine the carbamate compound with a pharmaceutical carrier. Theproportions of the carrier and carbamate compound are not critical, andthey can vary considerably depending on whether the composition is to befilled into capsules or formed into tablets. In tableting, it willusually be desirable to employ at least as much of the pharmaceuticalcarrier as the carbamate compound. Various edible carriers, or mixturesthereof can be used. For example, a mixture of lactose, dibasic calciumphosphate, and cornstarch is suitable. Additional ingredients can beincluded, such as lubricants like magnesium stearate.

When administering the compounds of this invention orally, the totaldaily dose will usually fall within the range from 400 to 2,400milligrams of the carbamate compound per 24 hour period. Typically, thedaily dose will range from 600 to 1,600 milligrams. In practicing themethod of this invention, it will therefore be convenient to have thecarbamate compound combined with a pharmaceutical carrier, such aslactose or dibasic calcium phosphate, and prepared in tablets or otherdosage unit form. Each tablet or dosage unit can contain from 50 to 600milligrams of the carbamate compound. For example, tablets containing200 milligrams of the carbamate compound can be administered one tabletthree times a day to achieve a daily dose of 600 milligrams, or up to 2tablets four times a day to achieve a daily dose of 1,600 milligrams.

The present invention is further illustrated by the following specificexamples.

EXAMPLE 1 A 500 ml. three-necked flask fitted with an addition funnel, amechanical stirrer, and a drying tube, was charged with 33.2 g. of1-phenyl-1,2-butanediol (0.2 mole), 16.2 g. of pyridine (.205 mole) and150 ml. of benzene. The flask was immersed in an ice bath. Ethylchiorocarbonate 22.2 g. (.205 mole) was added dropwise in a period ofminutes. The reaction mixture was then stirred at room temperature foranother two and one-half hours and left standing overnight.

100 ml. water was added to dissolve the pyridine hydrochloride formed.The benzene layer was separated, washed with water once, cold dilutehydrochloric acid twice, saturated NaHCO solution twice, and ice wateronce. It was then poured into 150 ml. of concentrated ammonium hydroxideat O". The reaction mixture was stirred at 0 for 2 hours. After thebenzene layer was separated, all the volatile material evaporated, alight yellow viscous oil, 40.5 g. was obtained. The crude product waspurified via column chromatography using alumina as the absorbent.Benzene and ether were used as the eluents. An orange viscous oil, 15.5g., was isolated from the benzene fraction and a semi-solid, 22.4 g.,was isolated from the ether fraction. The semi-solid was triturated withCCl to give crude P336, 9.9 g. It was recrystallized from CC], to whitecrystals, 7.3 g., M.P. 94.596, of l-hydroxyl-l-phenyl butyl Z-carbamate.

EXAMPLE 2 1-phenyl-1,2-propylene glycol, 15.2 g. (0.1 mole), was heatedat reflux with diethyl carbonate, 11.8 g. (0.1 mole), and mg. potassiumcarbonate. A Vigreux column was used to fractionate the ethanol formed.Heating was continued until temperature dropped at head (3 hours). Thecyclic carbonate was then distilled under vacuo, B.P. l50152/2 mm, 13.1g., a 74% yield.

The cyclic carbonate was stirred with 75 mm. of concentrated ammoniumhydroxide until all went into solution (one-half hour). After this,stirring was continued for one-half hour, the solvent was stripped off.The residue was azeotroped with benzene and recrystallized.l-hydroxy-l-phenyl butyl-Z-carbamate.

from benzene recovering 8.4 g., 43% based on glycol.

The carbamate was purified by hydrogenation using Pd on carbon as thecatalyst. Hydrogenation of 27 g. of carbamate was carried out inmethanol using 10 g. of 5% Pd on carbon catalyst at 45 lbs. H pressure.After a 1.5 lb. pressure drop, the reaction mixture was filtered. Thesolvent was stripped, and the residue recrysallized from 500 ml. ofbenzene, recovering 18 g. of the carbamate, M.P. 101102, ofl-hydroxy-l-phenyl-Z-propyl carbamate.

EXAMPLE 3 A 500 ml. three-necked fiask fitted with an addition funnel, amechanical stirrer, and a drying tube was charged with 30.4 g. ofl-phenyl-1,2-propanediol, 16.0 g. of pyridine, and 250 ml. of benzene.The flask was immersed in an ice bath. Ethyl chlorocarbonate, 21.8 g.was added dropwise in a period of three-fourths of an hour. The reactionmixture was then stirred at room temperature for 2 hours, washed with 50ml. of Water three times, and poured into 200 ml. of concentrated NI-IOH. The mixture was stirred overnight.

The benzene layer was separated and evaporated to dryness. The residuewas extracted with acetone. After the acetone solution was evaporated,the residue was treated with 200 ml. of benzene. P307, the isomericcarbamate, 4.5 g., M.P. 119-121" was isolated by filtration. Thefiltrate was concentrated and sent through an alumina column (750 g.).Benzene, acetone, and methanol were used as the eluents. From 1 liter ofacetone, 15 g. of product was isolated. Vacuum distillation gave twofractions. The high boiling fraction was the desired product,1-hydroxy-1-phenyl-2-propyl carbamate. It was redistilled to give anoil, 7.0 g., B.P. 1S7-161/0.4 mm.

EXAMPLE 4 Tablets for oral administration were prepared from Thiscompound was combined with a mixed pharmaceutical carrier in the ratioof 2 parts by weight of the carbamate compound per 3 parts of thepharmaceutical carrier. The mixed carrier contained dibasic calciumphosphate as the principal ingredient together with smaller amounts oflactose and 1 part of cornstarch. A small amount of magnesium stearatewas also included.

The carbamate compound, the calcium phosphate, the lactose, and part ofthe magnesium stearate were blended and dry mixed until a uniformcomposition was obtained. This was formed into firm slugs no greaterthan /4 inch thick. The slugs were then put through an oscillatinggranulator equipped with a 10 mesh screen. The cornstarch and a littlemore magnesium stearate were added at intervals while the slugs werebeing sized. The granulation was blended in a drum tumbler for 30minutes. Following this, the granulation was compressed into tablets of500 mg. per tablet containing 200 milligrams of the carbamate compound.

While in the foregoing specification this invention has been describedin relation to certain preferred embodiments and many details have beenset forth for purpose 60 of illustration, it will be apparent to thoseskilled in the art that the invention is susceptible to additionalembodiments, and that certain of the details set forth herein can bevaried considerably without departing from the basic principles of theinvention.

We claim:

1. A composition in dosage unit form for use as a short-acting sedative,comprising about 50 to 600 milligrams of a hydroxy phenyl alkylcarbamate compound in admixture with a pharmaceutical carrier, saidcompound containing a secondary alcohol group and having the structuralformula I ll @on-pn-o- NH2 wherein R is alkyl containing from 1 to 2carbon atoms.

5. The method of claim 4 wherein said compound is l-hydroxy-l-phenylbutyl-Z-carbamate.

6. The method of claim 4 wherein said compound is 1.-hydroxy-l-phenylpropyl-Z-carbamate.

7. The method of treating the central nervous system of an animal toobtain a sedative action therein, comprising orally administering tosaid animals from 400 to 2,400 milligrams per 24 hour period of ahydroxy phenyl alkyl carbamate compound containing a secondary alcoholgroup and having the structural formula wherein R is alkyl containingfrom 1 to 2 carbon atoms. 8. The method of claim 7 wherein said compoundis l-hydroxy-1-phenyl butyl-Z-carbamate.

9. The method of claim 7 wherein said compound is l-hydroxy-l-phenylpropyl-Z-carbamate.

References Cited by the Examiner UNITED STATES PATENTS 2,627,524 2/1953Malkemus 260-482 2,656,378 10/1953 Berger et a1. 260-482 2,724,72011/1955 Berger et al. 260-482 3,144,389 8/1964 Bossinger 16765 OTHERREFERENCES Berger, J. Pharm. and Exp. Ther. 104, page 230, 1952.

ALBERT T. MEYERS, Primary Examiner.

SAM ROSEN, Examiner.

4. THE METHOD OF TREATING THE CENTRAL NERVOUS SYSTEM OF AN ANIMAL TOOBTAIN A SEDATIVE ACTION THEREIN, COMPRISING ORALLY ADMINISTERING TOSAID ANIMAL A HYDROXY PHENYL ALKYL CARBAMATE COMPOUND CONTAINING ASECONDARY ALCOHOL GROUP AND HAVING THE STRUCTURAL FORMULA